Drugs which target serotonin receptors are useful for treating virtually every psychiatric disorder and many major medical disorders. The overall goals of this application are to determine how certain serotonin receptors (htr2A and htr2C) are regulated by the processes of neuronal targeting, trafficking and phosophorylation-induced post-translational processing. In the first two specific aims, the relevance of interactions with PDZ-domain proteins for controlling the neuronal targeting, trafficking and signaling of 5-HT2A and 5-HT2C receptors will be elucidated. For these studies we will use murine genetic deletion approaches (constitutive and conditional) and novel protein microarray-based approaches to discover and validate PDZ-domain protein interactions. We will also utilize in utero electroporation approaches and mouse genetic engineering approaches to determine how PDZ-binding motifs modulate 5-HT2A function in situ and in vivo. Similar studies may also be performed with 5-HT2C receptors. In the third specific aim we will determine if RSK2 modulates neuronal 5-HT2A receptor signaling and function in vitro and in vivo. In this specific aim we will utilize a variety of in vitro and in vivo approaches involving wild-type, 5-HT2A KO (constitutive and conditional) and RSK2 KO mice. We will clarify the role RSK2 plays in regulating 5-HT2A receptor signaling in neuronal and non-neuronal tissues in vitro and in vivo. Because these receptors are essential for the actions of many psychiatric and non-psychiatric medications including atypical antipsychotics, certain antidepressants, hallucinogens and some appetite suppressants our studies could lead to novel therapeutic strategies for many therapeutic indications. PUBLIC HEALTH RELEVANCE: Drugs which target serotonin receptors are useful for treating virtually every psychiatric disorder and many major medical disorders. This grant will elucidate the mechanisms by which serotonin receptors are targeted to different neuronal locations. This knowledge will help to clarify the mechanism by which these medications are effective in alleviating human illness.